1. Field of the Invention
The present invention relates to a sensor device of a microanalysis system (μ-TAS) for detecting a concentration, a fine pressure distribution, a fine temperature distribution, biological information, genetic information, and so forth of a substance flowing through a flow channel of the system.
2. Related Background Art
Recently, techniques are being developed for microanalysis in chemistry, biochemistry, and the like fields by use of a much smaller system. A typical example is a μ-TAS system which employs a micro flow channel, which enables separation/mixing, reactions, and so forth by a much smaller flow channel.
With development of biotechnology and bio-industry, detection elements like DNA chips are being developed and commercialized for reading bio-genetic information.
With the development of three-dimensional working techniques, chemical analysis systems are attracting attention which are constituted of liquid elements such as a micro flow channel, a pump, and a valve, and a sensor in integration on a substrate made of glass, silicon, or the like to conduct chemical analysis. Such a system is called a miniaturized analysis system, μ-TAS (micro total analysis system), or a lab-on-a-chip. The miniaturized chemical analysis system enables decrease of a dead volume in the system, remarkable decrease of a sample quantity, shortening of analysis time, and saving of power consumption of the total system. Further, cost-down of the system can be expected by the miniaturization. Owing to such advantages, the μ-TAS is promising in application in biotechnology fields such as in medical treatment like home medical care, and a bedside monitor; in biotechnology fields such as DNA analysis, and proteome analysis.
Japanese Patent Application Laid-Open No. H10-337173 discloses a micro-reactor which conducts sequential biochemical experimental operations of mixing solutions causing a reaction of the mixture, analyzing a component, and separating the component by employing combination of several cells. FIG. 11 shows schematically a structure of a micro-reactor. In FIG. 11, micro-reactor 1111 has independent reaction chambers closed by a flat plate on a silicon substrate. The reactor is constituted of reservoir cell 1112, mixing cell 1113, reaction cell 1114, detection cell 1115, and separation cell 1116. With plural reactors formed on a substrate, plural biochemical reaction can be simultaneously and concurrently conducted. Further, not only the analysis, but also a substance synthesis reaction such as protein synthesis can be conducted by use of the cells.
Such a μ-TAS system or a bib-chip requires a final detection step after the reaction or other operation steps. In the detection step, a light beam is useful as the precise detecting means less affective to the objective substance owing to non-contacting and non-reactive properties of the light.
In an example of the detection procedure, an objective substance is labeled with a fluorophor, an exciting light beam is projected to the objective substance, and the fluorescence is detected. In another example of the detection procedure, a light beam is projected to the objective substance, and light transmittance is measured. In still another example of the detection procedure, the light beam is projected to an objective substance through a prism brought close to the objective substance and the loss of the total reflection light is measured.
In the fluorescence labeling method, a desirable label, namely a label sufficiently sensitive for the detection, is not necessarily applicable owing to compatibility between the objective substance and the labeling substance. Further, in this method, the fluorescence as the signal component is interfered less by the intense exciting light as a noise because of the wavelength difference between the exciting light and the fluorescence advantageously, but the generation efficiency of the fluorescence as the signal component cannot readily be raised, which renders difficult to improve the total SN ratio.
In the light transmission measurement method or the light absorbance measurement method utilizing the transmitted light, when the objective substance is contained in a high concentration in the measurement fluid to exhibit a low transmittance, the signal is weak to result in a lower SN ratio. On the other hand, in this method, when the concentration of the objective substance is lowered to solve the above disadvantage, the original signal becomes weak to lower the SN ratio, also. Furthermore, even though the influence of the light is not remarkable, the light penetrating through the objective fluid may cause heat generation or a photoreaction, so that the intensity of the light should be limited.
In the total reflection loss measurement method, more intense light can be used than in the light transmission measurement method. However, the wavelength of the light for detection of a change or loss and the wavelength of the irradiated light are the same, which requires extremely large dynamic range of the detector, disadvantageously. Therefore, with this measurement method, a slight loss by a slight degree of reaction in the micro flow channel cannot be measured with a high accuracy.
On the other hand, a sensor device employing a photonic crystal, which has a high sensitivity, tends to detect an external disturbance as a noise component.
The external disturbance includes a fluctuation of a concentration, a temperature, and a density. The photonic crystal region itself and the substrate connected thermally to the photonic crystal region change in the temperature in various manners depending on the measurement operation environment. This is different from a high-cost or large-sized constitution which is equipped with a temperature-controlling feedback system, namely a temperature sensor, a heater/cooler element, a control circuit, or a power source. The constitution of small integration or a low cost cannot be equipped with such a temperature control means.
In particular, in a detection device in which a concentration of a biological substance as the objective substance in a solution flowing through a flow channel is measured, the measurement is conducted in a sequence of operation steps: (1) firstly a buffer solution containing no biological substance is allowed to flow through the flow channel, (2) secondly a buffer solution containing a biological substance is allowed to flow through the flow channel, and (3) finally a buffer solution containing no biological substance is allowed to flow through the flow channel to detect the difference from the initial level. In such an operation sequence, fluctuation of the concentration, temperature, or density of the buffer solution directly causes fluctuation of the baseline to produce a noise component. To decrease the temperature fluctuation, a means should be equipped for keeping the temperature constant in the aforementioned measurement region, and further a means should be equipped for keeping constant the temperature of the buffer solution before entering the measurement region. This causes a cost increase and a larger size of the device.